Genetics and ambient air pollutants are contributors to childhood respiratory diseases; however, gaps in the[unreadable] scientific knowledge base concerning the roles of specific sources, components and characteristics of air[unreadable] pollution and the role of inter-individual variation in susceptibility to air pollution's adverse effects impede[unreadable] effective intervention. The overall objective of the proposed program of research is to address these key[unreadable] gaps by investigating the contribution of genetics and exposure to air pollutants during childhood to the[unreadable] occurrence of asthma and deficits in lung function growth. Accordingly, the overall theme of the program[unreadable] project remains "Genetics, air pollution and children's respiratory health." The program of research proposed[unreadable] in this application builds on the rich health, exposure and genetic data resources of the Children's Health[unreadable] Study (CHS), an ongoing cohort study investigating both genetic and environmental factors related to[unreadable] children's respiratory disease in over 11,000 southern California children. The research hypotheses are[unreadable] based on mounting evidence that oxidant gases, traffic-related exposures and specific combustion-exhaust[unreadable] particle-bound constituents activate oxidative/nitrosative stress and inflammatory pathways and contribute to[unreadable] respiratory morbidity. Our research questions target the following health issues: (1) Are chronic respiratory[unreadable] health effects associated with exposure to near source combustion particles from vehicular exhaust? (2) Do[unreadable] PM mass in specific size fractions (PM[0.25], PM[0.25-2.5], and PM[2.5.-10]) or specific size-fractionated constituents[unreadable] (e.g., water-soluble or total organic carbon, elemental carbon, or selected transition metals) affect health? (3)[unreadable] Do genetic variants involved in innate or adaptive immune responses or nitrosative/oxidative stress[unreadable] pathways contribute to respiratory disease, deficits in lung development, or differences in susceptibility to the[unreadable] adverse effects of near source combustion products or regional gaseous or particulate pollutants? These[unreadable] questions will be investigated in three inter-related projects with support from three cores (Exposure[unreadable] Assessment, Integrative Health Sciences, and Biostatistics and Data Management). The projects will[unreadable] evaluate the relationship between respiratory health (asthma, lung function growth, exhaled NO) and[unreadable] combustion particulate and gaseous pollutants; examine genetic variation in key pathways that modulate[unreadable] response to air pollution and disease occurrence; and develop new biostatistical methods for GxE studies[unreadable] and integrated analysis across multiple outcomes and exposures. Building upon our large and wellcharacterized[unreadable] children's cohorts, rich exposure data, and substantial genetic resources, our collaborative[unreadable] multidisciplinary team will apply an integrative approach to efficiently address key gaps in the knowledge[unreadable] base needed for timely and effective disease prevention and treatment.[unreadable]